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68. Vandenput L, Boonen S, Van Herck E, Swinnen JV, Bouillon R, 77. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooper- Vanderschueren D 2002 Evidence from the aged orchidectomized berg C. Stefanick ML, Jackson RD, Beresford SA, Howard BV, male rat model that 17beta-estradiol is a more effective bone- Johnson KC, Kotchen JM, Ockene J 2002 Risks and benefits of sparing and anabolic agent than 5alpha-dihydrotestosterone. J estrogen plus progestin in healthy postmenopausal women: Prin- Bone Miner Res 17:2080-2086. cipal results From the Women’s Health Initiative randomized con- 69. Venken K, Boonen S, Van Herck E, Vandenput L, Kumar N, trolled trial. JAMA 288:321-333. Sitruk-Ware R. Sundaram K. Bouillon R. Vanderschueren D 2005 78. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Bone and muscle protective potential of the prostate-sparing syn- Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, thetic androgen 7alpha-methyl-19-nortestosterone: Evidence from Curb D, Gass M. Hays J, Heiss G, Hendrix S, Howard BV, Hsia the aged orchidectomized male rat model. Bone 36:663-670. J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, 70. Slemenda CW, Longcope C, Zhou L, Hui SL, Pcacock M, John- Kuller L. LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, ston CC 1997 Sex steroids and bone mass in older men. Positive Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Pren- associations with serum estrogens and negative associations with tice RL. Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefan- androgens. J Clin Invest 100:1755-1759. ick ML. Van Horn L, Wactawski-Wende J, Wallace R, Wasser- 71. Greendale G, Edelstein S, Barrett-Connor E 1997 Endogenous theil-Smoller S 2004 Effects of conjugated equine estrogen in sex steroids and bone mineral density in older women and men. postmenopausal women with hysterectomy: The Women’s Health The Rancho Bernard0 Study. J Bone Miner Res 12:1833-1841. Initiative randomized controlled trial. JAMA 291:1701-1712. 72. Van Pottelbergh I, Goemaere S, Kaufman JM 2003 Bioavailable 79. Smith CL, O’Malley BW 2004 Coregulator function: A key to estradiol and an aromatase gene polymorphism are determinants understanding tissue specificity of selective receptor modulators. of bone mineral density changes in men over 70 years of age. J Clin Endocr Rev 25:45-71. Endocrinol Metab 88:3075-3081. 80. Anonymous 1998 Tamoxifen for early breast cancer: An overview 73. Riggs BL, Khosla S, Melton LJ IT1 1998 A unitary model for of the randomised trials. Early Breast Cancer Trialists’ Collabo- involutional : Estrogen deficiency causes both type I rative Group. Lancet 351:1451-1467. and type 11 osteoporosis in postmenopausal women and contrib- 81. Johnell 0, Kanis JA, Black DM, Balogh A, Poor G, Sarkar S, utes to bone loss in aging men. J Bone Miner Res 13:763-773. Zhou C, Pavo I 2004 Associations between baseline risk factors 74. Eastell R 2007 Aromatase inhibitors and bone. J Steroid Biochem and vertebral fracture risk in the Multiple Outcomes of Raloxifene Mol Biol 106:157-161. Evaluation (MORE) Study. J Bone Miner Res 19:764-772. 75. Snyder PJ, Peachey H. Hannoush P, Berlin JA, Loh L, Holmes JH, 82. Seeman E, Crans GG, Diez-Perez A, Pinette KV, Delmas PD 2006 Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF. Haddad Anti-vertebral fracture efficacy of raloxifene: A meta-analysis. Os- JG Jr, Strom BL 1999 Effect of testosterone treatment on bone teoporos Int 17:313-316. mineral density in men over 65 years of age. J Clin Endocrinol 83. McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW Metab 84:1966-1972. 1995 Analysis of estrogen receptor function in vitro reveals three 76. Kenny AM, Prestwood KM, Marcello KM, Raisz LG 2000 Deter- distinct classes of antiestrogens. Mol Endocrinol 9:659469. minants of bone density in healthy older men with low testoster- 84. Chen J, Kim J, Dalton JT 2005 Discovery and therapeutic promise one levels. J Gerontol A Biol Sci Med Sci 55A:M492-M497. of selective androgen receptor modulators. Mol Interv 5:173-188.

Chapter 25.

Robert A. Nissenson’ and Harald Juppner2 ‘Endocrine Research Unit, VA Medical Center, Departments of Medicine and Phjwiology, University of California, Sun Francisco, California; ‘Endocrine Unit and Pediatric Nephrology Unit, Departments o,f Medicine and Pediatrics, Harvard Medical School, Massachusetts General Hospitcil, Bostoii, Mrrssachusetts

INTRODUCTION narrow limits over a wide range of dietary calcium intake. This chapter summarizes our current understanding of the biology The parathyroid glands first appear during evolution with the of PTH secretion and action. A nice historical perspective on movement of animals from an aquatic environment to a ter- this field has recently been published,(i) restrial environment deficient in calcium. Maintenance of ad- equate levels of plasma ionized calcium (1.0-1.3 mM) is re- quired for normal neuromuscular function, bone THE PTH POLYPEPTIDE FAMILY mineralization, and many other physiological processes. Chief Mammalian PTH is a single-chain 84 amino acid polypep- cells in the secrete PTH in response to very tide hormone that is expressed almost exclusively in the para- small decrements in blood ionized calcium to maintain the gland, with lesser expression in the rodent hypothala- normocalcemic state. As discussed later, PTH accomplishes mus and thymus. The appearance of PTH precedes that of the this task by promoting and releasing calcium parathyroid gland in evolution, because two forms of PTH from the skeletal reservoir; by inducing renal conservation of have been detected in teleosts that lack discrete parathyroid calcium and excretion of phosphate; and by indirectly enhanc- glands.(*.3) The physiological roles of PTH in fish have not yet ing intestinal calcium absorption by increasing the renal pro- been definitively established, although it has suggested based duction of the active metabolite 1,25(OH), vitamin on sites of expression that PTH may play a role in the devel- D. Serum ionized calcium and 1,25(OH), vitamin D produce opment of the teleost neural system, cartilage, and bone.(4) feedback inhibition of the secretion of PTH, whereas serum Teleost PTHs display significant amino acid homology to phosphate increases PTH secretion. The interplay between se- mammalian PTHs in the 1-34 sequence of the mature peptides rum calcium, PTH, 1,25(OH), vitamin D, and phosphate per- (i.e., the region required for binding to and activating the G- mit serum ionized calcium levels to be maintained within very protein-coupled PTHl receptor; Fig. 1).Teleosts display wide- spread expression of a PTHl receptor that presumably medi- The authors state that they have no conflicts of interest. ates the physiological actions of PTH.

0 2008 American Society for Bone and Mineral Research 124 I CHAPTER25

PTH, PTHrP, and TIP39 is reflected in the organization of the genes encoding these polypeptides (Fig. 2). PTH SYNTHESIS AND SECRETION There is a single mammalian PTH gene that in humans is present on the short arm of chromosome 11. The primary translation product is the precursor molecule prepro-PTH that includes a 25 amino acid pre sequence, a 6 amino acid pro IChickPTH PTH - sequence, and an 84 amino acid mature PTH sequence.(13)The zPTHl pre sequence functions as a signal sequence that directs the nascent polypeptide to the machinery that transports it across fPTHl the membrane of the endoplasmic reticulum (ER), where the - pre sequence is cleaved. The function of the pro sequence is not as clearly defined, but it seems to be required for efficient ER transport of the polypeptide and may play a role in sub- sequent events such as protein folding.(I4)The pro sequence seems to be cleaved by the protease furin, producing the ma- rPTHrP1 ture 1-84 PTH polypeptide. Once produced and packaged into secretory vesicles with the parathyroid chief cell, PTH( 1-84) is mPTHrP PTHrP subject to alternative fates. The mature hormone can be se- creted through a classical exocytotic mechanism or it may be hPTHrPJ cleaved by calcium-sensitive proteases present within secretory vesicles, resulting in the production and secretion of fragments of PTH(1-84) that lack the amino-terminal domain and are thus inactive with respect to responses mediated by the PTHl receptor."') Cleavage of circulating PTH( 1-84) to carboxyl- fragments can also occur in peripheral tissues such as liver and GIP "l kidney.' '') Historically, cleavage of PTH( 1-84) has been viewed as a mechanism for biological inactivation of the hor- FIG. 1. Phylogenetic analysis of PTH and related polypeptides."' mone, but there is suggestive evidence that carboxyl-terminal Copyright 2004, The Endocrine Society. fragments of PTH may display unique biological properties.'")

REGULATION OF PTH SECRETION BY PTH-related peptide (PTHrP) displays sequence homology EXTRACELLULAR CALCIUM with PTH that is limited to the amino-terminal 1-34 region of both peptides.'" PTHrP was originally identified as the hu- The major physiological function of the parathyroid glands moral mediator of hypercalcemia of malignan~y'~ and is is to act as a "calciostat," sensing the prevailing blood ionized now known to play a number of important physiological roles calcium level and adjusting the secretion of PTH accordingly (eg, control of endochondral bone development, smooth (Fig. 3). The relationship between ionized calcium and PTH muscle tone, and morphogenesis of the mammary gland).'x' secretion is a steep sigmoidal one, allowing significant changes The PTHrP gene has structural similarity to that of PTH, and in PTH secretion in response to very small changes in plasma the genes are presumed to be derived from a common ances- ionized calcium. The midpoint of this curve ("set-point") is a tral gene. This gene duplication event occurred at least five reflection of the sensitivity of the parathyroid gland to sup- hundred million years ago, as teleosts are known to express pression by extracellular calcium. homologs of mammalian PTHrP.(') PTH and PTHrP also dis- Alteration in plasma ionized calcium affects the secretion of play homology to TIP39 (tuberoinfundibular peptide of 39 PTH(1-84) by multiple mechanisms. Short-term increases in amino acids),'"') a factor that is expressed in the brain and extracellular ionized calcium produce increased levels of intra- testes and acts through the G-protein-coupled PTH2 recep- cellular free calcium in the parathyroid cell, resulting in acti- tor.(' ') Recently, TIP39 expression in the testis has been shown vation of calcium-sensitive proteases in secretory vesicles. As a to be essential for sperm development.('*) Homology amongst result, there is increased cleavage of PTH( 1-84) into carboxyl-

FIG. 2. Diagrammatic structures of the genes encoding human TIP39, PTH, and PTHrP. Boxed areas represent exons (the 5' end of exon U 1 in the TIP.39 gene is not known). White boxes denote pre se- quences, black boxes are pro sequences, gray stippled boxes are mature protein se- quences, and striped boxes are noncoding regions. The small striped boxes preceding the white boxes denote untranslated ex- onic sequences. The positions of the ini- tiator methionines are also indicated. +1 represents the relative position of the be- ginning of the secreted protein.'42) Copy- right 2002, The Endocrine Society.

0 2008 American Society for Bone and Mineral Research PARATHYROIDHORMONE I 125

terminal fragments. Increased extracellular calcium also inhib- its the release of stored PTH from secretory vesicles, although CALCIUM-REGULATED PTH RELEASE the molecular details of this regulation are not well defined. FROM NORMAL PARATHYROID CELLS Long-term changes in plasma ionized calcium (e.g., chronic dietary calcium deficiency) result in alteration in the expres- sion of the PTH gene and in the number of PTH-secreting I00 parathyroid cells. Extracellular calcium is sensed at the surface of the para- thyroid cell, and this leads to suppression of PTH secretion. Calcium sensing is initiated by the binding of calcium to a "sensing" receptor (CaR) present at high levels on the plasma membrane of parathyroid cells.('') Unlike intracellular cal- cium-binding proteins, which have an affinity for free calcium in the nanomolar range (consistent with intracellular levels of free calcium), CaR is presumed to bind free calcium with an 50 affinity in the millimolar range. CaR is a member of the G- protein-coupled receptor superfamily. It contains calcium binding elements in its extracellular domain and signaling de- terminants in its cytoplasmic regions. Calcium binding to CaR triggers activation of the G-proteins Gq and (to a lesser extent) Gi, resulting in stimulation of phos holipase C and inhibition of adenylyl cyclase, respectively." r.20) This results in an in- crease in intracellular calcium and a decrease in cyclic AMP levels in parathyroid cells. By mechanisms that are not fully defined, activation of these signaling pathways suppresses the 0 I .o 2.0'3.0 synthesis and secretion of PTH. When blood ionized calcium falls, there is less signaling by the CaRs on the parathyroid cell [ Ca+ +].mM and PTH secretion consequently increases. The essential role of the CaR can best be seen in humans bearing loss-of-function mutations in the CURgene. In the heterozygous state, such MAXIMUM I mutations result in familial hypocalciuric hypercalcemia 1 B. (FHH), characterized by inappropriately high levels of PTH secretion in the face of hypercalcemia.(21,22)These individuals are quantitatively resistant to the suppressive effect of calcium of PTH secretion because of the reduced number of parathy- roid CaRs. In the homozygous state, patients display a severe W m increase in PTH secretion with life-threatening hypercalcemia a (neonatal sevcre primary ). Mice with ho- W -I mozygous and heterozygous disruption of the CaR gene dis- w rn play similar phenotypes.(2') Of interest, deletion in mice of the I function of Gq and Gi, the G-proteins associated with CaR, k results in neonatal severe primary hyperparathyroidism, con- a firming the role of these G-proteins in CaR signaling.'241 Point mutations in the CaR that produce constitutive signaling have also been described, and these are associated with autosomal dominant hypocalcemia in human^.(*^.*^) Limited information is available on the mechanisms by 5 which CaR signaling suppresses PTH gene expression. Some MINIMUM studies suggest that transcription of the PTH gene is negatively regulated by calcium.'271 More recently, attention has been [ ca++] focused on the post-transcriptional effect of calcium to reduce the stability of PTH mRNA. Treatment of parathyroid cells FIG. 3. (A) Relationship between PTH secretion and extracellular with high calcium results in the binding of a protein factor(s) to calcium in normal human parathyroid cells. Dispersed parathyroid the untranslated regions of the PTH gene and to destabiliza- cells were incubated with indicated levels of calcium, and PTH was tion of PTH mRNA."") This effect seems to be mediated by determined by radioimmunoassay. [Reproduced with permission from Brown EM 1980 Set-point for calcium: Its role in normal and abnormal CaR-dependent increases in the level of intracellular free cal- parathyroid secretion. In: Cohn DV, Talmage RV, Matthews JL (eds.) cium.(2y)The identity of the relevant factor(s) remains to be Hormonal Control of , Proceedings of the Sev- established. enth International Conference on Calcium Regulating Hormones. Ex- Under normal physiological conditions, there is minimal cerpta Medica, Amsterdam, The Netherlands, pp. 35431. (B) The four proliferation of parathyroid cells. However, chronic hypocal- parameters describing the inverse sigmoidal relationship between the cemia elicits an increase in both the size and number of para- extracellular calcium concentration and PTH release in vivo and in thyroid cells.(30) Normalization of serum calcium suppresses vitro: maximal secretory rate; slopc of the curve at the midpoint; mid- the hyperplasia through signaling by CaR, although the mo- point or set-point of the curve (the level of calcium producing SO% of lecular details have not yet been worked out. the maximal decrease in secretory rate; minimal secretory rate.(431 Copyright 1983, The Endocrine Society. It is of considerable interest that CaR is expressed in a num- ber of tissues outside of the parathyroid gland including kid- ney, C-cells of the thyroid gland, gut, bone, cartilage, and many

0 2008 American Society for Bone and Mineral Research 126 I CHAPTER^^ others.(25)An important function of CaR in the kidney is to as a mediator of the effects of plasma phosphate on PTH se- signal the inhibition of calcium reabsorption in the cortical creti~n,(~~))although direct evidence is not currently available. thick ascending limb. This allows plasma calcium to regulate Further complicating matters is the observation that FGF23 renal calcium excretion independently of PTH, and a reduc- acts directly on the parathyroid gland to inhibit PTH secre- tion in this signaling contributes to the hypercalcemia and hy- ti~n.(~l)The integrated action of phosphate, FGF23, and a- pocalciuria seen in patients with FHH. Although the physi- Klotho on the parathyroid gland almost certainly constitutes a ological role of the CaR in other peripheral tissues is not well new and important physiological mechanism for the control of understood, recent studies with conditional knockout models PTH secretion. suggests that the expression of CaR in chondrocytes and os- teoblasts is essential for normal endochondral bone develop- REFERENCES ment (W. Chang, C. Tu, D. Bikle, and D. Shoback, personal 1. Potts JT 2005 Parathyroid hormone: Past and present. J Endocri- communication). no1 187:311-325. Several pharmacological agents that interact with CaR have 2. Hogan BM. Danks JA, Layton JE, Hall NE, Heath JK, Lieschke been developed, and these are effective in altering the ability GJ 2005 Duplicate zebrafish pth genes are expressed along the of the CaR to ~ignaI.'*~.~')So-called calcimimetic drugs bind to lateral line and in the central nervous system during embryogen- transmembrane regions in the CaR and increase the receptor's esis. 146547-551. sensitivity to extracellular calcium. This results in an increase 3. Gensure RC, Ponugoti B, Gunes Y, Papasani MR, Lanske B, Bastepe M, Rubin DA, Juppner H 2004 Identification and char- in receptor signaling and thus suppression of PTH secretion. acterization of two parathyroid hormone-like molecules in ze- Calcimimetic drugs have clinical utility in the medical manage- brafish. Endocrinology 145:1634-1639. ment of hyperparathyroidism. Calcilytic drugs act as pharma- 4. Guerreiro PM, Renfro JL, Power DM, Canario AV 2007 The cological antagonists of the CaR, reducing the receptor's sen- parathyroid hormone family of peptides: Structure, tissue distri- sitivity to calcium thus increasing the secretion of PTH.(32) bution, regulation, and potential functional roles in calcium and

ohosohate balance in fish. Am J Phvsiol ReedY Inteer" Como&, Phvs- lo1 292:R679-R696. REGULATION OF PTH SECRETION BY 1,25(OH), 5. Strewler GJ. Stern PH. Jacobs JW. Eveloff J, Klein RF. Leung SC, VITAMIN D Rosenblatt M, Nissenson RA 1987 Parathyroid hormonelikepro- tein from human renal carcinoma cells. Structural and functional For many years, it has been known that vitamin D deficiency homology with parathyroid hormone. J Clin Invest 80:1803-1807. is linked to excessive production of PTH. This is because of 6. Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley of JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, reduced suppression PTH secretion by extracellular calcium Chen EY, Hudson PJ, Martin TJ, Wood WI 1987 A parathyroid and by 1,25(OH), vitamin D. This frequently occurs in the hormone-related protein implicated in malignant hypercalcemia: setting of chronic renal failure where 1,25(OH), vitamin D Cloning and expression. Science 237:893-896. production is diminished, serum calcium is reduced, and phos- 7. Broadus AE, Mangin M, lkeda K, Insogna KL, Weir EC, Burtis phate levels are increased. As described below, hyperphospha- WJ, Stewart AF 1988 Humoral hypercalcemia of cancer. Identifi- temia has an independent effect to increase the secretion of cation of a novel parathyroid hormone-like peptide. N Engl J Med 319556-563. PTH. 8. Gensure RC, Gardella TJ, Juppner H 2005 Parathyroid hormone The suppression of PTH secretion by 1,25(OH), vitamin D and parathyroid hormone-related peptide, and their receptors. results from the inhibition of transcription of the PTH gene.(") Biochem Biophys Res Commun 328:666-678. This seems to involve 1,25(OH), vitamin D-induced binding 9. Abbink W, Flik G 2007 Parathyroid hormone-related protein in of the vitamin D receptor to negative regulatory elements in teleost fish. Gen Comp Endocrinol 152:243-251. the PTH gene promoter(34) and 1,25(OH), vitamin D-induced 10. Usdin TB. Hoare SR, Wang T, Mezey E, Kowalak JA 1999 TIP39: A new neuropeptide and PTH2-receptor agonist from hypothala- association of the vitamin D receptor with a transcriptional mus. Nat Neurosci 2941-943. repressor.(35) 1,25(OH), vitamin D and calcium act coordi- 11. Usdin TB, Dobolyi A. Ueda H, Palkovits M 2003 Emerging func- nately to suppress expression of the PTH gene and to inhibit tions for tuberoinfundibular peptide of 39 residues. Trends Endo- parathyroid cell proliferation. crinol Metab 14:1419. 12. Usdin TB, Paciga M, Kiordan T. Kuo J, Parmelee A, Petukova G, Camerini-Otero RD, Mezey E 2008 Tuberoinfundibular peptide REGULATION OF PTH SECRETION BY PLASMA of 39 residues is required for germ cell development. Endocrinol- PHOSPHATE, CY-KLOTHO,AND FIBROBLAST ogy 149:4292-4300. GROWTH FACTOR 23 13. Kemper B, Habener JF, Mulligan RC, Potts JT Jr, Rich A 1974 Pre-proparathyroid hormone: A direct translation product of It has long been known that hyperphosphatemia (as in parathyroid messenger RNA. Proc Natl Acad Sci USA 71:3731- chronic renal failure) is associated with parathyroid hyperpla- 3735. 14. Wiren KM, Ivashkiv L, Ma P, Freeman MW, Potts JT Jr, Kronen- sia and hyperparathyroidism. This effect of hyperphosphate- berg HM 1989 Mutations in signal sequence cleavage domain of mia is in part caused by the binding of plasma phosphate to preproparathyroid hormone alter protein translocation, signal se- free calcium, which lowers blood ionized calcium, thus stimu- quence cleavage, and membrane-binding properties. Mol Endo- lating PTH synthesis, secretion, and parathyroid cell num- crinol 33240-250. ber."6) However, serum phosphate also seems to directly af- 15. Habener JF, Kemper B, Potts JT Jr 1975 Calcium-dependent in- fect the parathyroid gland, increasin PTH synthesis by tracellular degradation of parathyroid hormone: A possible mechanism for the regulation of hormone stores. Endocrinology promoting the stability of PTH mRNA.&') 97:431441. In response to hyperphosphatemia, fibroblast growth factor 16. D'Amour P 2006 Circulating PTH molecular forms: What we 23 (FGF23) is secreted by osteocytes/osteoblasts and acts on know and what we don't. Kidney Int Suppl 102:S29-S33. the kidney to inhibit renal phosphate reab~orption.('~)This 17. Murray TM, Rao LG. Divieti P, Bringhurst FR 2005 Parathyroid requires the binding of FGF23 to cognate renal FGF receptors, hormone secretion and action: Evidence for discrete receptors for an interaction that requires a co-factor, namely the transmem- the carboxyl-terminal region and related biological actions of car- boxyl-terminal ligands. Endocr Rev 26:7&113. brane protein a-Kl~tho.(~')Interestingly, a-Klotho is also ex- 18. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor pressed in parathyroid cells, where it may promote PTH se- 0, Sun A, Hediger MA, Lytton J. Hebert SC 1993 Cloning and cretion through the maintenance of plasma membrane Na'/K' characterization of an extracellular Ca(2+)-sensing receptor from ATPase activity.(3') It has been suggested that a-Klotho serves bovine parathvroid. Nature 366575-580.

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19. Brown EM, MacLeod RJ 2001 Extracellular calcium sensing and Calcilytic compounds: Potent and selective Ca2+ receptor antago- extracellular calcium signaling. Physiol Rev 81:239-297. nists that stimulate secretion of uarathvroid hormone. J Pharmacol 20. Chang W, Chen TH, Pratt S, Shoback D 2000 Amino acids in the Exp Ther 299:323-331. second and third intracellular loops of the parathyroid Ca2+- 33. Silver J. Russell J, Sherwood LM 1985 Regulation by vitamin D sensing receptor mediate efficient coupling to phospholipase C. J metabolites of messenger ribonucleic acid ?or preprdparathyroid Biol Chem 27519955-19963. hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci 21. Pearce SH, Williamson C, Kifor 0,Bai M, Coulthard MG, Davies USA 82:4270-4273. M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, 34. Okazaki T. Igarashi T, Kronenberg HM 1988 S'-flanking region of Brown EM, Thakker RV 1996 A familial syndrome of hypocalce- the parathyroid hormone gene mediates negative regulation by mia with hypercalciuria due to mutations in the calcium-sensing 1,25-(OH)2 vitamin D3. J Biol Chem 263:2203-2208. receptor. N Engl J Med 335:1115-1122. 35. Kim MS, Fujiki R, Murayama A, Kitagawa H, Yamaoka K, Yama- 22. Pollak MR, Seidman CE, Brown EM 1996 Three inherited disor- moto Y.Mihara M, Takeyama K, Kato S 2007 IAlpha,25(OH)2D3- ders of calcium sensing. Medicine (Baltimore) 75:115-123. induced transrepression by vitamin D receptor through E-box-type 23. Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor 0, Warren HB, elements in the human parathyroid hormone gene promoter. Mol Brown EM, Seidman JG, Seidman CE 1995 A mouse model of Endocrinol 21:334-342. human familial hypocalciuric hypercalcemia and neonatal severe 36. Naveh-Many T, Rahamimov R, Livni N, Silver J 1995 Parathyroid hyperparathyroidism. 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Hu J, Spiegel AM 2007 Structure and function of the human cal- Nature 444:770-774. cium-sensing receptor: Insights from natural and engineered mu- 39. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A. tations and allosteric modulators. J Cell Mol Med 11:908-922. Obuse C, Togashi K, Tominaga M, Kita N. Tomiyama K, Iijima J, 27. Russell J, Sherwood LM 1987 The effects of 1,25-dihydroxyvita- Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, min D3 and high calcium on transcription of the pre-propara- Nozaki K. Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, thyroid hormone gene are direct. Trans Assoc Am Physicians Nabeshima Y 2007 alpha-Klotho as a regulator of calcium homeo- 100:25&262. stasis. Science 316:1615-1618. 40. Brownstein CA, Adler F, Nelson-Williams C, Iijima J. Li P, Imura 28. Moallem E, Kilav R, Silver J, Naveh-Many T 1998 RNA-Protein A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP binding and post-transcriptional regulation of parathyroid hor- 2008 A translocation causing increased alpha-klotho level results mone gene expression by calcium and phosphate. J Biol Chem in hypophosphatemic rickets and hyperparathyroidism. Proc Natl 2735253-5259. Acad Sci LJSA 1053455-3460. 29. Ritter CS, Pande S, Krits I, Slatopolsky E, Brown AJ 2008 Desta- 41. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, bilization of parathyroid hormone mRNA by extracellular Ca2+ Mohammadi M, Sirkis R, Naveh-Many T, Silver J 2007 The para- Role of and the calcimimetic R-568 in parathyroid cells: cytosolic thyroid is ti target organ for FGF23 in rats. J Clin Invest 117:4003- Ca and requirement for gene transcription. J Mol Endocrinol 4008. 40:13-21. 42. John MR. Arai M, Rubin DA, Jonsson KB, Juppner H 2002 Iden- 30. Cozzolino M, Brancaccio D, Gallieni M, Galassi A, Slatopolsky E, tification and characterization of the murine and human gene en- Dusso A 2005 Pathogenesis of parathyroid hyperplasia in renal coding the tuberoinfundibular peptide of 39 residues. Endocrinol- failure. J Nephrol 18:S-8. ogy 143:1047-1057. 31. Steddon SJ, Cunningham J 2005 Calcimimetics and calcilytics- 43. Brown EM 1983 Four-parameter model of the sigmoidal relation- fooling the calcium receptor. Lancet 365223772239. ship between parathyroid hormone release and extracellular cal- 32. Nemeth EF, Delmar EG, Heaton WL, Miller MA, Lambert LD, cium concentration in normal and abnormal parathyroid tissue. J Conklin RL, Gowen M, Gleason JG, Bhatnagar PK, Fox J 2001 Clin Endocrinol Metab 56572-581.

Chapter 26. Parathyroid Hormone-Related Protein

John J. Wysolmerski Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

INTRODUCTION PTHrP and PTH are related molecules that can both stimulate the same type I PTH/PTHrP receptor (PTHlR)."-" PTHrP In a 1941 case report in the New England Journal of Medicine, usually a local autocrine, or intracrine role Fuller Albright first postulated that tumors associated with and normally does not circulate. However, in patients with hypercalcemia might elaborate a PTH-like humor,(^) Work in the 1980s and 1990s subsequently led to the biochemical char- HHM, PTHrP does reach the and the 'YS- acterization of a specific syndrome of humoral hypercalcemia temic actions of PTH. Another chapter will discuss malig- of malignancy (HHM) and the fulfillment of Albright's pre- nancy-associated hypercalcemia in detail. This chapter will dictions by the isolation of PTH-related urotein (PTHrP) and outline the normal PhYsiol%Y of PTHrP. the charaiterization of its gene.""' We now understand that

Key words: parathyroid hormone-related protein, bone, nuclear The author states that he has no conflicts of interest. transport. cartilage. mammary gland. vascular smooth muscle

0 2008 American Society for Bone and Mineral Research